The general and long-term goal of my laboratory is to study autoantibody- mediated skin diseases in order to further our understanding not only of the pathophysiology of these diseases but also of the structure and function of normal epidermis and epidermal basement membrane zone. Specifically, antibodies in these diseases define molecules in the normal epidermis. We are characterizing the antigens defined by three of these diseases: bullous pemphigoid (BP), pemphigus vulgaris (PV), and pemphigus foliaceus (PF). BP antigen is known to be a component of the hemidesmosome, a basal cell-substrate adhesion junction. We have determined, with immunochemical methods, that the BP antigen is a 230 kD protein with a pI of 8. With antibody screening of a lambda gt11 expression cDNA library derived from cultured human keratinocytes, we have isolated a partial cDNA clone encoding the C-terminal end of this antigen. In order to find a cDNA with the full length coding sequence, we have used portions of this partial cDNA as primers and probes to construct and screen new cDNA libraries. We have thus cloned overlapping cDNAs encoding almost the total molecule. Antibodies raised against fusion proteins and synthetic peptides from sequences coding the carboxy-domain bind the hemidesmosome plaque, inside basal cells, as determined by immunoelectron microscopy. Analysis of protein structure and amino acid sequence indicates marked homology with desmoplakin I, a desmosome plaque protein. These studies indicate that BP antigen and desmoplakin I form a gene family of adhesion plaque proteins. We have also characterized, by immunochemical methods, the PV and PF antigen complexes extracted from normal human epidermis, and shown that they contain the adhering junction molecules desmoglein (PF antigen) and plakoglobin (both antigens). Thus, in diseases of defective cell adhesion, autoantibodies are directed against adhering junction components. Patients with drug-induced pemphigus have antibodies against these same molecules.